Key Piece of Melanoma Puzzle Found

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A protein that helps cells produce pigment appears to hold the key to creating more effective treatments for melanoma, according to researchers at The University of Manchester.

The protein, MITF, enables cancer cells to resist MEK inhibitors, a new category of drugs that has shown less success than expected during clinical trials.

That explains why human melanoma cells that didn't respond to an MEK inhibitor contained much higher levels of the protein SMURF2, in a comparison of such cells to human melanoma cells that did respond carried out by a team led by Claudia Wellbrock, Ph.D., at the Wellcome Trust Centre for Cell-Matrix Research.

In mice with tumors, researchers found, tumor growth showed a substantial decrease over three weeks when SMURF2 was removed along with MEK inhibitors. However, when researchers reduced the level of SMURF2 in the melanoma cancer cells, then treated the tumor with the MEK inhibitor, they found a 100-fold increase in the sensitivity of the cells to the drug.

Researchers concluded that removing SMURF2 dramatically decreased the level of MITF in melanoma cells, making the MEK inhibitor much more powerful. Results of the study, funded in part by Cancer Research UK, have been published in the Journal of the National Cancer Institute.

“Cancers frequently find new ways to combat even the most novel and highly efficient drug treatments, so we are now focusing on targeting the mechanisms that allow the cancer cells to overcome the drug effects,” Dr. Wellbrock said in a statement. “The development of resistance to new drugs has also been a major drawback. If we can identify more potent and less toxic drug combinations to tackle melanoma then we could save thousands of lives."

Next research steps for Dr. Wellbrock’s team will entail finding a drug that can reduce the activity of SMURF2 in cancer cells. The team is now screening drug libraries in hopes of repurposing an existing drug that may already be approved for use for a different illness. The goal is to identify a drug for use with MEK inhibitors in order to provide a much more powerful and ultimately more successful approach to treating melanoma.

New approaches to overcoming drug resistance in attacking melanoma will be a key focus of the UK’s planned new Manchester Cancer Research Centre, created to develop personalized cancer treatments. Construction of the center’s new research building began last month.